2. Academic Validation
  3. Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models

Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models

  • J Med Chem. 2022 Feb 24;65(4):3306-3331. doi: 10.1021/acs.jmedchem.1c01871.
Jon J Winter-Holt,  Catherine Bardelle 1,  Elisabetta Chiarparin,  Ian L Dale,  Paul R J Davey,  Nichola L Davies,  Christopher Denz 2,  Shaun M Fillery,  Carine M Guérot,  Fujin Han 3,  Samantha J Hughes,  Meghana Kulkarni 2,  Zhaoqun Liu 3,  Alexander Milbradt,  Thomas A Moss,  Huijun Niu 3,  Joe Patel,  Alfred A Rabow,  Marianne Schimpl,  Junjie Shi 3,  Dongqing Sun 3,  Dejian Yang 3,  Sylvie Guichard 2
Affiliations

Affiliations

  • 1 BioPharmaceuticals R&D, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • 2 Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 3 Pharmaron Beijing Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
PMID: 35133824 DOI: 10.1021/acs.jmedchem.1c01871
Abstract

ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit. The result is compound 5 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast Cancer models.

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